Acenaphthene derivatives

ABSTRACT

Acenaphthene derivatives are provided having the general structure: WHEREIN R and R&#39;&#39; are alkyl having from one to about three carbon atoms. These compounds possess anti-inflammatory activity.

United States Patent Levine 51 July 25, 1972 [54] V ACENAPH' IHENE DERIVATIVES [72] Inventor: Seymour D. Levine, North Brunswick, NJ.

[73] Assignee: E. R. Squibb & Sons, Inc., New York,

[22] Filed: Dec. 23, 1969 [21] Appl. No.: 887,735

Beilstein s Handbook of Organic Chemistry, vol. 7, pp. 3798- 3799 1969).

Smith, Open Chain Nitrogen Compounds, vol. 2, pp. 31-

Primary Examiner-Leon Zitver Assistant Examiner-Gerald A. Schwartz AttorneyLawrence S. Levinson, Merle J. Smith, Donald J. Perrella and Burton Rodney [57] ABSTRACT Acenaphthene derivatives are provided having the general structure:

wherein R and R are alkyl having from one to about three carbon atoms. These compounds possess anti-inflammatory activity.

4 Claims, No Drawings ACENAPHTHENE DERIVATIVES The present invention relates to acenaphthene derivatives and more particularly to acenaphthenequinone dialkoximes having anti-inflammatory activity as well as cardiovascular and central nervous system activity and sunscreening properties.

The compounds of this invention are useful as anti-inflammatory agents and are effective in the prevention and inhibition of granuloma tissue formation in warm-bloodedanimals, for example, in a manner similar to indomethacin. They may be used to decrease joint swelling tenderness. pain and stiffness, in mammalian species, e.g., in conditions such as rheumatoid arthritis. A compound of Formula I (below) may be compounded according to accepted pharmaceutical practice in oral dosage forms such as tablets, capsules, elixirs or powders for administration of about 100 mg. to 2 gm. per day, preferably 100 mg. to 1 gm. per day in two to four divided doses.

The acenaphthenequinone derivatives of the invention have the general formula:

wherein R and R can be the same or different and are alkyl having from one to three carbon atoms, such as methyl, ethyl, propyl or isopropyl.

Exemplary of the compounds falling with the present invention are the acenaphthenequinone dimethoximes, acenaphthenequinone diethoximes, acenaphthenequinone dipropoximes, l-methoximino-Z-ethoximinoacenaphthenequinone and l-methoximino-Z-propoximinoacenaphthenequinone,

The compounds of the invention can be prepared by reacting acenaphthenequinone with an excess of alkoxyamine hydrohalide and a base in the presence of a solvent for the reactants.

The base can be an Organic base or an inorganic base such as pyridine, sodium acetate, potassium acetate, sodium hydroxide, potassium hydroxide or cesium hydroxide. Pyridine is preferred inasmuch as it serves as both a base and a solvent.

in addition to pyridine, the solvent can be an alcohol containing up to about four carbon atoms, such as methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, n-butyl alcohol, sec. butyl alcohol or tert. butyl alcohol. Dimethyl sulfoxide may also be employed as a solvent.

The alkoxyamine hydrohalide can be methoxyamine hydrochloride, ethoxyamine hydrochloride, n-propoxyamine hydrochloride, isopropoxyamine hydrochloride, methoxyamine hydrobromide, ethoxyamine hydrobromide, n-propaxyamine hydrobromide or isopropoxyamine hydrobromide.

ln carrying out the above reaction, the alkoxyamine hydrohalide should be employed in a weight ratio to the acenaphthenequinone (alkoxyamine hydrohalidezacenaphthenequinone) within the range of from about 1:] to about :1 and preferably from about 1:1 to about 4: l.

The reaction of the acenaphthenequinone and alkoxyamine hydrohalide can be carried out at room temperature. However, if desired, higher temperatures, ranging from about 25 to about 100 C. and preferably from about 25 to about 50 C. may be employed to expedite reaction. Temperatures higher than 1002 C. can be employed, however, with no apparent benefit.

The compounds of the invention may be in the form of one or more geometric isomers, one symmetrical form and one unsymmetrical form, which can be depicted as follows:

Thus, for example, acenaphthenequinone dimethoxime can have the following structures:

and

and

Example 1 Acenaphthenequinone Dimethoximes A mixture of 5 g. of acenaphthenequinone and 5 g of methoxyamine hydrochloride in ml. of pyridine is warmed to achieve solution and then allowed to stand at room temperature overnight. The mixture is poured into water, and the resulting precipitate is collected by filtration. A chloroform solution of the solid is washed with 2N hydrochloric acid, 8 percent salt solution, dried (Na SO and evaporated. The residue is crystallized from isopropyl ether-hexane to give a mixture of acenaphthenequinone dimethoximes, 4.1 g., m.p. l24-l 30. The mixture is separated by plate chromatography on silica gel using chloroform-hexane (lzl as the developing solvent. Crystallization of the less polar product from isopropyl ether gives a symmetrical acenaphthenequinone dimethoxime, m.p. l46.5-l47.5; 5%|, 5.70 (s, NOCH l.73 (q, 7.13, 0.91 cps, ortho protons).

Anal. Calcd for C,,H,,N,0,= c, 69.99; H, 5.03;

N, 11.66. c, 69.70; H, 5.06; N, ll.60.

Found:

Anal. Calcd for C H N- O C, 69.99; H, 5.03;

N, ll.66. C, 70.l3; H, 5.06; N. [1.67.

Found:

Example 2 Acenaphthenequinone Diethoximes pyridine is stirred at room temperature overnight. The mixture 3,679,747 3 4 In a manner similar to that described in Example I, but sub- ]l;N\ NOClh stituting ethoxyamine hydrochloride 'for methoxyamine hydrochloride, a mixtures of isomers of the title compound is obtained.

Example 3 0 0 l-Methoximino-Z-ethoximinoacenaphthenequinone A mixture of 1.0 g. of acenaphthenequinone and 458 mg. of I methoxyamine hydrochloride in 20 ml. of pyridine is stirred at room temperature overnight. The mixture is poured into water and the resulting precipitate collected by filtration to give 0.82 g. of acenaphthenequinone monomethoxime. Cm N N l0 3. lsomers of acenaphthene derivatives in accordance with claim I having the structural formula:

A mixture of 0.82 g. of acenaphthenequinone monomethoxime and 600 mg. of ethoxyamine hydrochloride in 20 ml. of

is poured into water and the resulting precipitate collected by filtration to give the title compound.

What is claimed is:

1. An acenaphthene derivative having the structural formula selected from the group consisting of and o and O v w l wherein R and'R' are the same and are alkyl having from one to three carbon atoms.

2. An acenaphthene derivative in accordance with claim 1 having the structural formula:

4. An acenaphthene derivative in accordance with claim I g wherein R and R are ethyl. 3

I l k 3 UETTED STATES PATENT OFFICE v CERTIFICATE OF CORRECTION QA26 Patent No. 4 v Dated y 1972 inventofls) Seymour D. Levine Itvi-s certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, line 59, "npropax-" should read nprdpox- Column l, line 71, "higher than 1002 C." should read -higher than-lOOC.-.

Column 2, line 38, "in the opinion of l inventor" should read -in the opinion of the inventor--.

Signed and sealed this 1st day of May 1973..

(EAL?- Attest:

ElJJTCI-IIJR, JR. RUBERT (IO'IT'ISCH L LK .Ittesting Officer Commissioner of Patents 

2. An acenaphthene derivative in accordance with claim 1 having the structural formula:
 3. Isomers of acenaphthene derivatives in accordance with claim 1 having the structural formula:
 4. An acenaphthene derivative in accordance with claim 1 wherein R and R'' are ethyl. 